Method and apparatus for treatment of congestive heart failure by improving perfusion of the kidney by infusion of a vasodilator

ABSTRACT

A method for treating congestive heart failure (CHF) has been developed that restores kidney renal functions by artificial vasodilation of at least one kidney. A vasodilator drug is locally delivered to the kidney via a kidney perfusion catheter. The drug can be mixed with the patient&#39;s blood, saline or other suitable solvent and the mixture directly applied to the kidney through the catheter. The restoration of kidney function assists the heart by removing excess fluid, urine and toxin from the patient, and by normalizing the patient&#39;s renin-angiotensin system and other neurohormonal substances. The method is applicable to treat chronic and acute CHF.

FIELD OF THE INVENTION

The invention generally relates to the treatment of kidneys by directapplication of a vasodilator agent. In particular, the invention relatesto a method and apparatus to treat patients with congestive heartfailure by reducing resistance to blood flow to the patient's kidney bydirect infusion of a vasodilator drug.

BACKGROUND OF THE INVENTION

A. Congestive Heart Failure

Congestive heart failure (CHF) is a serious condition affecting anestimated 5 million Americans. Increasing prevalence, hospitalizations,and deaths have made CHF a major chronic health condition in the UnitedStates. There are an estimated 400,000 new cases of CHF each year. Thesecases are often first diagnosed as the end stage of cardiac disease. Theaverage mortality rate of CHF is 10 percent after the 1st year and 50percent after 5 years. Thus, half of the patients diagnosed with CHFwill die within 5 years of their diagnosis.

The magnitude of the problem is expected to get much worse as morecardiac patients are able to survive and live longer. As patients livelonger, the potential for developing CHF increases. In addition, becausethe incidence of heart failure rises substantially beyond age 65, theprevalence of this condition is likely to increase as the populationages.

The high prevalence of heart failure and the resulting high cost ofcaring for these patients places a significant economic burden onsociety. The American Heart Association statistics report that,including medications, an estimated $22.5 billion will be spent for thecare of CHF patients in hospitals, physicians offices, home care, andnursing homes including medications in the year 2000. In light of thehigh costs and poor prognosis of CHF, there is a pressing need toprevent this condition and provide better clinical management to reducemorbidity and mortality.

Congestive heart failure (CHF) is a diseased condition in which theheart fails to function efficiently as a pump to provide sufficientblood flow and/or pressure to fulfill the normal circulatory needs of apatient. CHF results in sudden shortness of breath, fainting andirregular heart beats that require frequent emergency room treatments(acute CHF), and in its chronic form leads to repeated hospital stays,deteriorating quality of life and significant costs to the health caresystem. Congestive heart failure is characterized by: (1) signs andsymptoms of intravascular and interstitial volume overload, includingshortness of breath, fluid in the lungs, and edema, and (2)manifestations of inadequate tissue perfusion, such as fatigue or poorexercise tolerance. These signs and symptoms result when the heart isunable to generate a cardiac output sufficient to meet the body'sdemands.

In CHF, the failing heart is not able to generate sufficient bloodpressure to properly perfuse the kidneys, e.g., provide sufficient bloodpressure to force blood through the kidneys and filter the blood. In apatient suffering from chronic heart failure, the blood pressure tendsto progressively decrease as the heart progressively fails over weeks,months or years. With the decrease in blood pressure there is aconcomitant decrease in organ perfusion. Accordingly, chronic heartfailure can lead to chronic impaired renal perfusion.

Chronic heart failure patients frequently evolve into acute CHF and areadmitted to hospital with an abrupt worsening of their condition. Duringthese periods of acute hypotension (or low blood pressure) their kidneysarc particularly at risk from decreased renal blood flow and may beseverely injured. In some cases the blood pressure of these patients canbe normal but at the expense of the total shutdown of the blood flow tothe kidneys.

B. Relationship of Kidney Failure to CHF

The kidneys are a pair of organs that lie in the back of the abdomen oneach side of the vertebral column. They play an important regulatoryrole in maintaining the homeostatic balance of the body. The kidneysfunction like a complex chemical filtering plant. They eliminate foreignchemicals from the body, regulate inorganic substances and theextracellular fluid, and function as endocrine glands, secretinghormonal substances like renin and erythropoietin.

The main functions of the kidney are to maintain the water balance ofthe body and control metabolic homeostasis. The kidneys regulate theamount of fluid in the body by making the urine more or lessconcentrated, thus either reabsorbing or excreting more fluid,respectively. The kidneys also extract undesirable chemicals andconcentrate them in urine, while allowing the reabsorption of otherchemicals.

The kidney processes of filtration, reabsorption and fluid regulationtake place in the renal nephron of the kidney. Within the nephron thesmallest circulatory vessels, capillaries and arterioles, form aglomerulus. The glomerulous is intimately associated with the renaltubules to filter wastes from the blood, remove excess water from thebody and produce concentrated urine. The glomerular filtration rate(GFR) is a clinical indicator universally accepted as a measure of theability of the kidney to remove fluid and solutes. GFR is the summary ofthe physiologic functions of the kidneys.

The kidneys remove the deleterious metabolic products from the blood,which represents a small portion of the total blood volume. The blood isrepeatedly circulated through the kidney several times during each dayto remove the required amount of these deleterious metabolic products.In a healthy person, the kidney receives approximately 10% of thecardiac output which is the total body blood flow (about 0.5 liters perminute) which, over the course of a day, amounts to 720 liters per dayof blood passing through each kidney. Significantly more blood fluid isfiltered through the kidneys than is excreted as urine. Most of thefiltered blood fluid must be reabsorbed into the circulatory system tomaintain the fluid balance of the body.

Without properly functioning kidneys, a patient will suffer waterretention, reduced urine flow and an accumulation of wastes toxins inthe blood and body. These conditions resulting from reduced renalfunction or renal failure (kidney failure) are believed to increase theworkload of the heart. In a CHF patient, renal failure because ofdecreased renal perfusion will cause the heart to further deteriorate.Water and blood toxins accumulate due to the poorly functioning kidneysand in turn, cause the heart further harm.

Fluid overload during CHF is caused in two ways. First, activation ofneurohormonal mechanisms of the renin-angiotensin system and aldosteroneactivation leads to peripheral vasoconstriction and retention of salt,thus water by the kidney. Second, the persistent lower renal blood flowand pressure cannot generate adequate hydrostatic pressure to makesufficient urine to remove excess retained fluid. Accordingly, thekidneys are a principal non-cardiac cause of a progressive fluidoverload condition in a patient suffering from CHF.

Patients with CHF can also suffer episodes of acute, severedeterioration caused by abrupt decreases in heart function. Theseepisodes are characterized by rapid reductions in blood pressure andflow, especially to the kidney. Similarly to the chronic state, acutelyreduced kidney perfusion can result in a sudden, massive retention offluid leading to pulmonary edema (fluid in lungs). This acute fluidoverload taxes an already overburdened heart and can lead to theseverest of complications: acute renal failure and death.

C. Prior Kidney Treatments for CHF

To treat CHF, the physicians must fight the body's attempt to inflictitself harm. Physicians can treat the patient with medications thatimprove the pumping ability of the heart, increase blood pressure andattempt to reactivate a more normal behavior of the body's control(homeostatic) system. Heart failure patients are put on a strict lowsodium diet and their fluid intake is monitored. Some patients arelimited to as little as one liter of fluid a day. Diuretics are a classof drugs that combat fluid overload. Diuretics affect the kidneyfunction in such a way that the reabsorption of fluid is suppressed. Asa result there is more urine output contrary to neurohormonal commandsthat the kidney is receiving.

When diet, diuretics, and other treatments can no longer achieveadequate fluid removal with existing kidney function, renal replacementtherapies such as hemofiltration or dialysis have been increasingly usedas a method of removing fluid in the acute CHF state. Acute heartfailure can be treated with the Continuous Renal Replacement Therapy(a.k.a. an artificial kidney or dialysis machine) in the ICU (intensivecare unit) of a hospital. A dialysis machine is instrumental in reducingfluid overload and preventing such complications as pulmonary edema.However, the dialysis machine can be harmful to other organs and doesnot protect the kidney itself from further deterioration from thepersistently low blood pressure and poor perfusion caused byvasoconstriction of the renal artery and arterioles (smaller branches).Further, renal replacement therapy may be used to remove fluid but isassociated with significant complications. Renal replacement is limitedsince it may cause further abrupt reductions in blood pressure, actuallyworsening the heart failure state and further renal dysfunction.Physicians are also reluctant to use replacement therapy in unstablepatients because of added risk of hypotension.

Continuous hemofiltration is based on the well-established therapy withan artificial kidney (or renal replacement therapy). Blood iscontinuously extracted from the body, passed through an artificialkidney machine and then returned back to the body. In thishemofiltration process, some of the undesired chemicals can be extractedfrom the blood. Most importantly for acute heart failure patients, fluidcan be filtered out of the blood stream in a slow controlled infusionwhile concentrating the blood.

Reversing fluid overload can improve heart function and significantlyenhance the clinical status of the CHF patient. While therapies, such ashemofiltration, remove fluid from the patient, they can actually lead tolower blood pressure, further deterioration of the heart and ultimatelyrenal failure requiring the patient to undergo permanent dialysis orkidney transplant.

D. Vasodilators in Heart Failure

Until recent years, the therapy of heart failure was devoted torestoring contractility with cardiac glycosides and relieving congestionand edema with diuretics. The additional use of vasodilating agents hasbeen shown to be valuable where conventional therapy alone has beenineffective. The role of vasodilators as first line agents is now morefirmly established.

In a CHF, the reduction in cardiac output causes the peripheralresistance to rise in the vascular system in order to maintain perfusionpressure to vital organs. This compensatory increase in peripheralresistance is mediated by increased sympathetic tone and angiotensin.This compensatory response sets up a vicious circle whereby a loweredcardiac output leads to vasoconstriction, which, in turn, furtherreduces cardiac output as the heart fails to cope against the increasedperipheral resistance. Arterial vasodilators administered to CHFpatients lower aortic impedance (afterload) and, thus, reduce theworkload of the heart. This results in a reduced ventricularend-diastolic volume, pressure and wall tension. If the blood vesselsare dilated the amount of work needed for the heart to pump bloodforward is decreased and heart efficiency enhanced. Administeringsystemic vasodilators either orally or added directly to the bloodstreamvia a bolus IV injection or drip is beneficial to the CHF patient andparticularly important to the kidney function. Vasodilatation of renalblood vessels results in increased renal plasma flow, improved renalfunction, and reduction of the secretion of renin.

Unfortunately in severe heart failure the conventional treatments usingvasodilators is limited. The weakened heart has a reduced ability topump blood and cannot maintain adequate blood pressure. Since the heartcan no longer augment its force of contraction, any increase invasodilation, while beneficial in reducing the work and preserving theheart, has an adverse effect on vital organ perfusion and survival ifprolonged. For example, a disadvantage of the conventional treatment ofsystemic administration, oral or intravenous, is that vasodilatorsremain in the bloodstream for a prolonged amount of time (until thevasodilators are metabolized or excreted). In view of the problemsassociated with prolonged retention only very limited amounts ofvasodilators can be given to the patient without a risk of severecomplications. Even at low or normal doses, commonly clinically usedvasodilating agents (such oral compounds as captopril, enalapril orother known class of dilator such as nitroglycerin or the intravenouslyadministered compound sodium nitroprusside) effect the peripheralcirculation of blood to the patient's arms, legs, and other peripheralareas. These vasodilating agents reduce systemic vascular resistanceand, with a weakened heart incapable of adequately responding to demand,can cause severe hypotension and circulatory collapse.

SUMMARY OF INVENTION

Because of the limited success of the above kidney treatments, there isa long-felt need to be able to treat the fluid overload complications ofCHF by restoring natural kidney functions, and without resorting tomechanical kidney dialysis. Restoration of natural kidney functionswould advantageously: (1) return kidney function to normal thereforeprotecting kidney from hypotension induced damage, (2) remove excessfluid volume from a patient in a safe controlled manner, and/or (3)alter a patient's neurohormonal environment. Restoring natural kidneyfunctions in a CHF patient should decrease or eliminate some of thephysical signs and symptoms of congestive heart failure, and improve apatient's quality of life and survival rate. There is a need to have avasodilator therapy where the chemical agent will be delivered directlyand only to the kidney and will be removed from circulation or loose itspotency upon leaving the kidney or shortly thereafter so that the restof the peripheral circulation will not be effected.

One of the challenges to developing a new kidney therapy is the largeamount of blood that passes through the kidney and quickly circulatesthrough the rest of the body. With the kidney receiving as much as 10%of the total cardiac output a locally administered drug will withinminutes be returned to the heart and distributed throughout thecirculatory system. Therefore, slowly metabolized vasodilators willcontinue circulating until the net adverse effect from the localdelivery is the same as if the drug was infused systemically.

Also, the systemic blood pressure and flow to a patient's kidney may beinsufficient, even in the setting of vasodilator therapy, to allowclinical benefit from the vasodilator therapy. In other patients, theblood flow to the kidney may not be interrupted for prolonged periods oftime without causing severe injury. Thus, some patients may also requirecontinuous perfusion of the kidney during infusion of vasodilatortherapy to maintain viability of the kidney.

The invention is a kidney treatment which reduces the kidney'sresistance to blood flow. The treatment allows for greater perfusion ofblood through the kidney. The invention applies a vasodilation agentdirectly to a kidney using a kidney perfusion catheter. The perfusioncatheter is inserted at the entrance to the renal artery and provides aflow of blood at an elevated pressure to perfuse the kidney. Avasodilation agent is added to the perfusion blood flow and, thus, flowsdirectly to the perfused kidney. The vasodilation agent relaxes thekidney so that the vessels through the kidney dilate. The dilatedvessels reduce the resistance of the kidney to the perfusing blood flowand allow a greater volume of blood to flow through the kidney.

The invention includes a novel method and apparatus of treating acuteand chronic CHF by reduction of the vascular resistance of the bloodvessels inside the kidney by infusing a vasodilating agent. Vasodilationis achieved by administration of a vasoactive substance such asnitric-oxide (NO) continuously over a period of time that will yield thedesired clinical effect (removal of excessive fluid and normalization ofkidney function).

The vasodilator while dissolved in blood, saline or other substancecapable of binding the molecules of the vasodilating agent is deliveredto the kidney directly via a catheter. The vasodilator breaks downquickly when in contact with blood so that the systemic vasodilationwill not follow the vasodilation of the kidney.

SUMMARY OF THE DRAWINGS

A preferred embodiment and best mode of the invention is illustrated inthe attached drawings that are described as follows:

FIG. 1 is a graphical illustration of a patient being treated for CHF byperfusing a kidney with a perfusion catheter and blood pump with acoupled local drug delivery system;

FIG. 2 is a diagram illustrating a catheter perfusion system with a NOgas exchanger;

FIG. 3 is a diagram illustrating a drug delivery system without aperfusion pressure delivery system;

FIG. 4 is an implantable pump for delivery of vasodilator connected to arenal artery;

FIG. 5 is a flow chart for a method of vasodilating a patient's kidneywith local drug delivery to achieve a desired condition of the patient;

FIG. 6 is a flow diagram of the compensatory cycle of congestive heartfailure; and

FIG. 7 is a flow diagram and illustration of the remedial effects ofdirect vasodilator therapy on the cycle of CHF.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION

FIG. 1 shows one embodiment of the proposed therapy where thevasodilator drug is used in combination with the apparatus for perfusionof the kidney with a percutaneous catheter. A method and apparatus forisolated perfusion of a kidney with a catheter is described more fullyin the co-owned and related U.S. patent application Ser. No. 09/454,605,filed Dec. 7, 1999, for a “Kidney Perfusion Catheter”; and U.S. patentapplication Ser. No. 09/501,234, filed Feb. 10, 2000, for a “Method andApparatus for Treatment of Congestive Heart Failure by ImprovingPerfusion of the Kidney”, both of which applications are still pending.The disclosures of both of these patents are incorporated by reference.

FIG. 1 is a schematic diagram of a patient 1 having a heart 2, an aorta3 a femoral artery 4, a kidney 5, and a renal artery 6. A perfusioncatheter assembly 8 is inserted at the patient's groin 13 and into thefemoral artery. The catheter, e.g., introducer catheter 14, ismaneuvered by a surgeon through the femoral artery, into the aorta tothe entrance (ostium 12) of one of the renal arteries 6. The distal endof catheter may include a sealing balloon 16 to block off the entranceof the renal artery and position the catheter at the ostium. Similarly,a positioning balloon 17 may position the catheter within the arota.

Blood enters a proximal end 9 of the catheter from a blood pump 10 andflows from the distal end 11 of the catheter (which may include smalldiameter catheter tip 15 that extends past the ostium and into the renalartery) directly into the renal artery. Upon exiting the pump, blood ismixed with the fluid containing the vasodilator drug. A drug couplingdevice 24 connects the drug dispersing apparatus 18 to the proximal end9 of the catheter, such that the drug can be infused into the bloodflowing from the pump 10 to the catheter.

A known dose of the drug is preloaded into an automatic syringe pump 20and infusion syringe 21. A controller apparatus with a motor 22 isprogrammed to dispense the drug at a constant rate prescribed by aphysician. An optional feature is blood flow rate feedback monitor 23.The rate of the discharge of the drug infusion pump 20, as controlled bythe controller 22, can be continuously adjusted based on the rate of theperfusion pump 10. The concentration of the drug in the blood infusedinto the kidney can be maintained in an amount sufficient to causevasodilation and be therapeutically effective.

A vasodilator drug is selected for the effective and safe utilization ofthe treatment would have to have an exceptionally short life after itenters the kidney. Nitric-oxide (NO) is a vasodilator that fits thisrequirement. After being dissolved in blood, NO is rapidly scavenged byblood cells and remains active only for 8 to 10 seconds. Nitric-oxide(previously called an endothelial derived relaxing factor) is aphysiologic regulator of renal hemodynamics. Nitric-oxide is a highlydiffusible, reactive free radical. In the body, it is produced in thevascular endothelium and diffuses to the adjacent vascular smooth musclewhere it causes vasodilation. Nitric-oxide is continually produced at abasal level in many locations throughout the kidney. Because of theshort half-life of nitric-oxide, the location of nitricoxide generationis a major determinant of its site of action. Within the renalcirculation, nitric-oxide generated by basal endothelial synthesisvasodilates afferent (pre-glomerular) resistance, efferent(post-glomerular) resistance and the mesangial (important for the rateof filtration) cells. Nitric-oxide therefore increases plasma flow,affects glomerular capillary pressure (PGC) and increases coefficient ofultrafiltration (Kf) by mesangial cell relaxation leading to increase inglomerular filtration rate.

Nitric-oxide is naturally generated by the kidneys to dilate bloodvessels and reduce vascular resistance to blood flow. Nitric-oxide isreleased continuously from endothelial cells in the basal state. Therate of nitric-oxide release increases with increasing blood flow. Asthe blood flow increases, the shear stress increases due to the bloodflowing across the inner surface of the arterial wall. The shear stresson the endothelial cells of the vessel walls stimulates those cells togenerate nitric-oxide. As a result, increased amounts of nitric-oxide,among other vasoactive substances, are released. These vasoactivesubstances cause the arterial smooth muscle vasculature to relaxresulting in a flow induced arterial vasodilation. In addition toactively vasodilating the contractile cells of the kidney, nitric-oxidealso opposes active vasoconstrictor influences which would otherwiseincrease the resistance of the kidney to perfusion. Chronic inhibitionof nitric-oxide production produces sustained hypertension and renalvasoconstriction, with the eventual development of kidney damage.

NO is widely available in the practice of medicine as gas stored incylinders under pressure. It has been successfully used in respiratorymedicine by mixing the small amounts into the oxygen containing gasmixture administered to the patient by a ventilator. U.S. Pat. No.5,957,880 discloses an extracorporeal flow circuit (such as acardiopulmonary bypass machine) where one or more nitric-oxide feeds toprovide a concentration of nitric-oxide in the blood effective toinhibit activation of blood platelets and reduce whole body inflammationof the patient induced as a result of a procedure using theextracorporeal circulation. A membrane filter permeable to NO but not tothe blood is used to mix NO into the blood. These techniques forinfusing NO into a fluid flow from the pump to the catheter are welldeveloped. Such techniques are used in extracorporeal membraneoxygenators to transport oxygen into the blood. These techniques may beused to introduce NO into the blood flow as it is circulated through ablood pump.

FIG. 2 shows a kidney catheter assembly 31 with an attachment tointroduce nitric-oxide (NO) or other vastrodilator agent into theperfusion fluid flow to a kidney. The cylinder with NO gas 26 provides apositive pressure that infuses NO into the solution through a membrane27. The infusion of the vastrodilator may be used in conjunction with ablood infusion. NO is forced into a gas compartment 28 of the gasexchange chamber 29. A gas permeable membrane 27 allows molecules of NOto migrate into the blood stream but is not permeable to bloodcomponents. Such permeable membranes are well known in the oxygenationof blood and used in heart lung machines and extracorporeal bloodoxygenators (ECMO). If NO transfer is from gas to blood a hydrophobicmembrane with pores large enough to allow molecules of gas to pass butsmall enough to stop the water, proteins and other components of bloodfrom passing. If the NO is dissolved in fluid and the molecules aretransferred across the membrane using osmotic pressure gradient, thehydrophilic membrane will be used. Suitable hydrophilic membranes arewell known and used in dialysis filter for artificial kidney to exchangemolecules of chemicals between the blood and the dialysate solution.Such membranes often are manufactured as micro pore fiber bundles andare available for example from Minntech (Minneapolis, Minn.).

To dilute NO it can be mixed with a carrier gas such as Nitrogen orHelium. The pump 10 is the means for regulating the blood flow andprefusion pressure applied to the kidney, and for and indirectlyregulating the rate of flow for delivering the nitric oxide gas in anamount sufficient for causing renal vasodilation. In addition a pressureregulator on the cylinder can be used to adjust the flow of gas.

NO is dissolved in a transport solution, e.g., a kidney perfusion fluid,that is biocompatible with blood. Blood is one example of asolvent-transport fluid, but other possible solvent-transport fluids forthe delivery of NO to the kidney include, isotonic saline and Krebssolution. The Krebs-Ringer solution is a modification of Ringer'ssolution, prepared by mixing NaCl, KCl, CaCl2, MgSO₄, and phosphatebuffer. Since NO is toxic in high concentrations, the unused quantity ofgas can be collected into a vacuum chamber 30. NO is harmless ifreleased later into atmosphere. A simple pressure regulator can be usedto control flow of NO gas into the filter 27 while the speed of the pump10 can be used to maintain the desired kidney perfusion pressure. Inthis way both the kidney vascular resistance and perfusion pressure canbe manipulated to achieve the desired renal blood flow that is thedetermining factor of the kidney function (GFR).

FIG. 3 shows another embodiment of a drug dispensing apparatus 18 whereNO or other vasodilator drug is dissolved in a solution. For NO, asolute can be as simple as sterile saline or a more complex andspecialized compound such as a fluorocarbon emulsion. One representativeof blood-type fluorocarbon emulsions is Fluosol manufactured in Japan byGreen Cross Corporation and consisting of Perfluorodecalin,Perflurotripropylamine (oxygen carriers), surfactants, and osmoticbalance ions. Fluosol has capacity to bind the nitric oxide that isseveral times higher than that of water or saline. Newer Perfluro Carbonemulsions that can bind NO and Oxygen and are more bio-compatible thanFluosol were disclosed in detail in the U.S. Pat. No. 5,869,539. Thesolution is in the container 32 and flows through the pump into thecatheter 33. The catheter 33 is non-occluding drug delivery catheter andcan be as small as 1 mm in diameter. The infusion pump 34 slowly infusesthe solution into the renal artery. Substantial blood flow going fromaorta into the kidney will pick up the substance and carry it downstreaminto the kidney.

Restoration of acceptable renal resistance by the local delivery ofvasodilator applied directly applied to one or both kidneys of a patientwith heart failure significantly improves renal blood flow, removesexcess body fluids and improve the patient's overall condition. Inaddition, restoring renal blood flow to the kidney suppresses thedeleterious activation of the renin-angiotensin system and theconsequences of its widespread adverse effects on CHF patients as isshown in FIG. 7.

FIG. 4 shows an implanted embodiment of the present invention. A batteryoperated microprocessor controlled pump 51, similar to known insulininjection pumps, is subcutaneously implanted in the body. An internalkidney catheter 52 is grafted to the renal artery 6. NO or othervasodilator drug is dissolved in the fluid contained in the reservoirinside the pump. Periodically the reservoir can be refilled bypuncturing the patient's skin with a syringe. A special port on the pumpreceives the injection and seals after the needle is withdrawn.

FIG. 5 is a flow chart for a method of infusing the vasodilator into thepatient's kidney to achieve a desired condition of the patient. Thevasodilator drug is infused into the patient's renal artery such asusing a kidney perfusion catheter apparatus shown in differentembodiments in FIGS. 1 through 4, in step 20. During the treatment ofthe vasodilator, the patient is continually monitored, in step 21, todetermine whether the desired clinical outcome has been obtained. Forexample, the desired clinical outcome may be increased urine output fromthe patient. There may be other desired clinical outcomes, such assufficient decrease in water retention, changes in blood pressure, orother conditions of the patient which can be clinically monitored by thedoctor and that reflect effective treatment by the vasodilator drug.

If the desired clinical outcome is not obtained in a reasonable amountof time, as determined by the doctor, then in step 22 the drug infusionrate is adjusted and the vasodilator treatment is continued. Monitoringof the patient continues and the doctor or other healthcare professionalcontinues to determine whether the desired clinical outcome has beenattained. Accordingly, a cycle is set up in which the vasodilatorinfusion rate is adjusted, possibly on several occasions, until thedesired clinical outcome is attained in the patient. When the desiredclinical outcome is attained in the patient, the vasodilator treatmentand kidney perfusion treatment is terminated in step 23. The patient isfurther monitored to confirm that the patient is able to maintainsufficient renal perfusion naturally without the assistance of thekidney perfusion catheter. If natural renal perfusion does not occur,then the kidney perfusion therapy and the infusion of the vasodilatordrug is resumed in step 20. Preferably, the patent is able to maintainrenal perfusion naturally, in step 24, so that both the kidney perfusiontherapy and the infusion of vasodilator drugs can be discontinued.Although not shown in FIG. 5, the doctor may at any time discontinue thevasodilator treatment if such treatment is deemed ineffective.

FIG. 6 illustrates the hemodynamic impairment resulting from CHF.Impaired heart function 100 results in a decreased cardiac output,decreased peripheral blood pressure and diminished organ perfusion 102and 108. The decrease in blood flow and consequent decrease in renalblood perfusion 102 activates several neurohomonal systems 104, such asthe rennin-angiotensin and aldosterone system, sympatho-adrenal systemand vasopressin release. As the kidneys suffer from increased renalvasoconstriction, the filtering rate (GFR) of the blood drops and thesodium load in the circulatory system increases 106. Simultaneously,more renin is liberated from the juxtaglomerular of the kidney 104. Thecombined effects of reduced kidney functioning include reducedglomerular sodium load, an aldosterone-mediated increase in tubularreabsorption of sodium, and retention in the body of sodium and water106. These effects lead to several signs and symptoms of the CHFcondition, including an enlarged heart (ventricular dilation), increasedsystolic wall stress and an increased myocardial oxygen demand 107, andthe formation of edema on the basis of fluid and sodium retention in thekidney. Accordingly, sustained reduction in renal blood flow andvasoconstriction is directly responsible for causing the fluid retentionassociated with CHF.

FIG. 7 is a chart illustrating the remedial effects of direct renalinfusion of a vasodilator. Increased fluid removal results from therestoration of renal blood flow 110 across the kidney by decreasingrenal vascular resistance through renal vasodilation 110. Restoringrenal perfusion 111, should result in increased urine output 112 and adecrease in the neurohormaonal stimulation 113 caused by kidneys in afailing condition. This decrease in stimulation by the kidneys isexpected to decrease the vasoconstriction 114 in the patient'scirculatory system, and decrease the amount of sodium and fluidretention 115 in the patient. In turn, increased urine output, reducedvasoconstriction, and decreased sodium level should restore normal fluidbalances in the patient, improve oxygenation of the blood and decreasethe heart workload 116. Heart function should improve 117 due to thereduction in its workload and the other beneficial effects due to renalperfusion. Moreover, a stronger heart and higher blood pressure willimprove the perfusion of other organs 118 and thereby normalize theacid-base metabolism 119 to further improve the workload on the heart.

The level of effectiveness of this method is substantially above thelevels achieved by systemic (IV or oral) drug therapy. A primaryadvantage of this method over other modalities is that the vasodilatorcompound is administered directly and locally to the kidney's arterialvasculature. This minimizes any untoward effects caused by systemicvasodilation and resultant increases in hypotension. In addition, afurther advantage of this method is that the fluid overload in thepatient is remediated by restoring the patient's own kidney function.This avoids relying on artificial kidney devices for hemofiltration orhemodialysis to remove excess body fluid and metabolic wastes.

The system for treating CHF disclosed here restores kidney functioningand thereby breaks the cycle between heart and kidney failure. Thistreatment may be used in connection with other CHF treatments thatdirectly treat the heart, and may be used for both chronic and acuteCHF.

The invention has been described in connection with what is presentlyconsidered to be the most practical and preferred embodiment. Theinvention is not limited to the disclosed embodiment. The inventioncovers various modifications and equivalent arrangements included withinthe spirit and scope of the appended claims.

What is claimed is:
 1. A method for treatment of a patient sufferingfrom reduced kidney function comprising the steps of: a. directlyinfusing at least one kidney of the patient with a fluid containingnitric oxide; b. by the application of the nitric oxide, increasingblood flow through the at least one kidney with resulting restoration ofrenal function of said kidney to a predetermined renal function level;c. after the nitric oxide passes through said at least one kidney, avasodilator effect of said nitric oxide is reduced and does not causeincreased blood flow through other body organs of the patient, and d.ceasing the infusion of nitric oxide after the predetermined renalfunctional level has been achieved.
 2. A method of treatment of apatient having congestive heart failure comprising the steps of: a.directly infusing at least one kidney of the patient with a fluidcontaining nitric oxide; b. by the application of the nitric oxide,increasing blood flow through the at least one kidney with resultingrestoration of renal function of said kidney to a predetermined renalfunction level; c. after the nitric oxide passes through said at leastone kidney, a vasodilator effect of said nitric oxide becomes reducedand does not cause increased blood flow through other body organs of thepatient, and d. ceasing the infusion of nitric oxide after thepredetermined renal functional level has been achieved, wherein steps(a), (b) and (c) are repeated on a periodic basis to treat congestiveheart failure.
 3. A method as in claim 1 comprising the further step ofperfusing the at least one kidney.
 4. A method as in claim 1 wherein thefluid includes a carrier fluid.
 5. A method as in claim 4 wherein thecarrier fluid is selected from a group consisting of a saline solution,a krebs-ringer solution and a fluorocarbon emulsion.
 6. A method oftreatment of a patient having inadequate renal function comprising thesteps of: a. preparing a vasodilator fluid by infusing a gas comprisingnitric oxide into a carrier fluid externally of the patient; b. directlyinfusing at least one kidney of the patient with the vasodilator fluid;c. increasing blood flow through the kidney with resulting restorationof renal function of said kidney to a predetermined renal functionlevel; d. ceasing the infusion of the vasodilator fluid after thepredetermined renal functional level has been achieved.
 7. A method oftreatment of a patient suffering from inadequate renal functioncomprising the steps of: a. preparing an artificial vasodilator fluid byinfusing a nitric oxide gas into a carrier fluid externally of thepatient; b. directly infusing at least one kidney of the patient withthe vasodilator fluid; c. increasing blood flow through the kidney withresulting restoration of renal function of said kidney to apredetermined renal function level; d. ceasing the infusion of theartificial vasodilation fluid after a predetermined renal functionallevel has been achieved.
 8. A method as in claim 7 wherein the nitricoxide gas is infused through a membrane in contact with the carrierfluid at a rate dependent on a pressure of a nitric oxide gas source influid communication with the membrane.
 9. A method to treat congestiveheart failure in a patient comprising the steps of: a. directly infusingat least one kidney in the patient with a fluid containing a nitricoxide; b. increasing of blood flow through the kidney after step (a); c.ceasing step (a) after a predetermined renal functional level has beenachieved, or a predetermined time of treatment has elapsed.
 10. A methodto treat congestive heart failure as in claim 9 wherein steps (a), (b),and (c) are repeated on a periodic basis to treat chronic congestiveheart failure.
 11. A method to treat congestive heart failure in apatient comprising the steps of: a. infusing at least one kidney in thepatient with a fluid containing nitric oxide; b. ceasing the nitricoxide infusion step after a predetermined renal functional level hasbeen achieved, or a predetermined time of treatment has elapsed.
 12. Amethod to treat congestive heart failure as in claim 11 wherein steps(a) and (b) are repeated on a periodic basis to treat chronic congestiveheart failure.
 13. A method to treat a kidney in a patient havinghypotension induced damage comprising the steps of: a. infusing thekidney with a fluid containing a vasodilator fluid comprising nitricoxide and a carrier fluid; b. increasing of blood flow through thekidney after step (a); c. after the nitric oxide passes through thekidney, a vasodilator effect of said nitric oxide becomes reduced anddoes not cause increased blood flow through other body organs of thepatient, and d. ceasing step (a) after renal function has been restored.14. A method as in claim 13 wherein step (a) is performed on said kidneyand said patient has a second kidney that is not infused.
 15. A methodas in claim 13 wherein renal function restoration is determined by thepatient achieving a predetermined renal functional level.
 16. A methodas in claim 13 wherein renal function restoration is determined by thepatient achieving an increase in urine output.
 17. A method as in claim13 steps (a) and (b) are repeated on a periodic basis to treat recurringhypotension.
 18. A method to treat chronic heart failure in a patientcomprising the steps of: a. infusing a renal artery of the kidney with afluid containing a nitric oxide, and b. increasing of blood flow throughthe kidney after step (a), wherein the nitric oxide becomes inactive inthe patient promptly after flowing through the kidney.
 19. A method asin claim 18 wherein the nitric oxide is scavenged by blood in thepatient.
 20. A method as in claim 18 wherein the nitric oxide becomesinactive before inducing systemic hypotension throughout the patient.21. A method as in claim 4 wherein the carrier fluid is blood taken fromthe patient and further comprising the step of infusing nitric oxide gasinto the blood externally of the patient.
 22. A method as in claim 21wherein the nitric oxide gas is mixed into the blood through asemi-permeable membrane externally of the patient.
 23. A method as inclaim 4 wherein the carrier fluid is plasma taken from the patient andfurther comprising the step of infusing the nitric oxide into the plasmaexternally of the patient.
 24. A method as in claim 1 wherein the nitricoxide is substantially eliminated from blood with 10 seconds afterinfusion into the kidney.
 25. A method of treatment of a patient havingreduced renal function comprising the steps of: a. preparing avasodilator solution comprising nitric oxide and carrier fluid; b.infusing the vasodilator solution into at least one kidney of thepatient; c. the infusion of the vasodilator solution increases bloodflow through the at least one kidney with resulting restoration of renalfunction of said kidney; d. ceasing the artificial vasodilatation stepafter a predetermined renal functional level has been achieved.
 26. Amethod of treatment of a patient suffering from reduced kidney functioncomprising the steps of: a. infusing at least one kidney of the patientwith a vasodilator solution comprising nitric oxide that releases allnitric oxide upon contact with blood in the kidney, and b. ceasingreleasing nitric oxide after the blood treated with the infusion of saidvasodilator solution passes through the infused kidney.